Molecular mediators of cardiac-specific enhancer activation

Abstract

Understanding how transcription factors (TFs) control gene expression programs is critical for determining the genetic pathways responsible for development. Heart development is particularly sensitive to precise control of gene programs as faulty regulation leads to congenital heart defects (CHD), the leading cause of infant mortality. Although sets of TFs have known roles in heart development, in most cases, we lack a fundamental understanding of how these binding events regulate cell specification. To identify potential key regulatory TFs, we used the Assay for Transposase-Accessible Chromatin (ATAC-seq) to map changes in chromatin accessibility and integrated these data with maps of histone modification patterns and gene expression across several stages of embryonic stem cell (ESC) differentiation toward cardiomyocytes (CMs). Based on bioinformatic analysis of these data, we identified the TEA domain family (TEAD) TF TEAD1 as a candidate regulator of enhancer activation during cardiac-lineage commitment. We then used an inducible degron-tag strategy to conditionally deplete TEAD1 and observed an abnormal beating phenotype in CMs. Further mechanistic studies revealed that TEAD1 was necessary for the activity of a subset of cardiac enhancers putatively linked to cell-cell contacts. These data have allowed us to characterize a potential link between extracellular signaling and cardiac contraction and morphogenesis during development.